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Cough | GSK2339345 Hypertussive Challenge Study

Cough research study

What is the primary objective of this study?

This study is designed to evaluate the effect of GSK2339345 relative to placebo on the number
of coughs in patients with Chronic Idiopathic Cough (CIC) administered by an Aqueous Droplet
Inhaler (ADI). The primary aim is to investigate the efficacy of GSK2339345 on reducing
objective cough frequency in CIC patients. The secondary aim of this study is to investigate
the efficacy of GSK2339345 in inhibiting a hypertussive cough response elicited by capsaicin
and citric acid in CIC patients which have a hyperresponsive cough reflex.
Following the screening visit, all eligible subjects will attend the unit for dosing at
Visits 1-7. At Visits 1, 2 and 3 (Part A of the study), subjects will receive two doses of
either GSK2339345 or placebo, 4 hours apart and will undergo 8 hours of cough monitoring. At
Visits 4 and 5 (Part B of the study) and Visits 6 and 7 (Part C of the study), subjects will
be administered a single dose of either GSK2339345 or placebo. Subjects will then undergo
capsaicin (Part B) or citric acid (Part C) tussive challenge and will undergo cough
monitoring for 1 hour post dose.
The maximum study duration will be approximately 11 weeks, including 3 weeks screening and 2
weeks follow-up. Approximately 30 patients will be randomised into the study, such that
approximately 24 patients complete dosing and critical assessments.

Who is eligible to participate?

Inclusion Criteria
- Chronic Idiopathic Cough patients according to the criteria listed below, determined
by a responsible and experienced physician, based on a medical evaluation: Idiopathic
cough defined as chronic cough resistant to treatment targeted at potential triggers.
Chronic cough defined as cough lasting for more than 8 weeks.
- A patient with a clinical abnormality or laboratory parameters outside the reference
range for the population being studied may be included only if the Investigator and
the GSK Medical Monitor agree that the finding is unlikely to introduce additional
risk factors and will not interfere with the study procedures.
- Male/females aged >=18 years old, at the time of signing the informed consent.
- Non-smoker for at least 6 months with a cumulative history of <= 10 pack years. Pack
years = (No. of cigarettes smoked/day/20) x (No. of years smoked).
- Body weight >= 50 kilograms.
- A female subject is eligible to participate if she is of; Non-childbearing potential
defined as pre-menopausal females with a documented tubal ligation or hysterectomy
[for this definition, \"documented\" refers to the outcome of the
investigator's/designee's review of the subject's medical history for study
eligibility, as obtained via a verbal interview with the subject or from the subject's
medical records]; or postmenopausal defined as 12 months of spontaneous amenorrhea [in
questionable cases a blood sample with simultaneous follicle stimulating hormone > 40
milli international unit/milliliter (mL) and estradiol < 40 picogram/ml (<147
picomoles/Liter [L]) is confirmatory]. Females on hormone replacement therapy (HRT)
and whose menopausal status is in doubt will be required to use one of the
contraception methods if they wish to continue their HRT during the study. Otherwise,
they must discontinue HRT to allow confirmation of post-menopausal status prior to
study enrollment. For most forms of HRT, at least 2 to4 weeks will elapse between the
cessation of therapy and the blood draw; this interval depends on the type and dosage
of HRT. Following confirmation of their post-menopausal status, they can resume use of
HRT during the study without use of a contraceptive method.
Child-bearing potential with negative pregnancy test as determined by serum human chorionic
gonadotropin test at screening or prior to dosing and Agrees to use one of the
contraception methods for an appropriate period of time (as determined by the product label
or investigator) prior to the start of dosing to sufficiently minimize the risk of
pregnancy at that point. Female subjects must agree to use contraception until the follow
up visit or has only same-sex partners, when this is her preferred and usual lifestyle.
- Male subjects with female partners of child-bearing potential must agree to use one of
the contraception methods. This criterion must be followed from the time of the first
dose of study medication until the follow up visit.
- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.
- Aspartate amino transferase and alanine amino transferase < 2xupper limit of normal
(ULN); alkaline phosphatase and bilirubin <= 1.5xULN (isolated bilirubin >1.5xULN is
acceptable if bilirubin is fractionated and direct bilirubin <35%).
- Based on averaged QT interval corrected (QTc) values of triplicate electrocardiograms
(ECGs) obtained over a brief recording period: QTc using Fridericia's formula (QTcF) <
450 millisecond.
- A 24 hour Holter ECG at screening that demonstrates no clinically significant
abnormalities or finding that could interfere with interpretation of the study
results, when assessed by an appropriately trained and experienced reviewer.
Exclusion Criteria Based Upon Medical Histories
- Subjects who have evidence of current asthma, as confirmed by the Investigator or
designee.
- Subjects with any clinically significant respiratory condition or lung pathology that
could cause cough (apart from chronic idiopathic cough).
- Known lung cancer or other active malignancy, or history of.
- Subjects with current or a chronic history of cardiovascular disease (including
uncontrolled hypertension, ischemic heart disease, angina, myocardial infarct,
congestive heart failure, and stroke).
- Subjects with current central nervous system / peripheral nervous system conditions
e.g. epilepsy and myasthenia gravis.
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
- Any subject with a respiratory tract infection within 4 weeks of screening.
- Radiological imaging prior to the study, including chest X-rays, that have shown any
evidence of clinically significant lung disease, as judged by the Investigator or
designee.
- History of regular alcohol consumption within 6 months of the study defined as an
average weekly intake of >21 units for males or >14 units for females. One unit is
equivalent to 8 grams of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass
(125 mL) of wine or 1 (25 mL) measure of spirits.
- Any subject who has a history of an allergic reaction to a local anesthetic. History
of sensitivity to any of the study medications, or components thereof or a history of
drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline
(GSK) Medical Monitor, contraindicates their participation.
- Any subject who has a known hypersensitivity to capsaicin or citric acid. Exclusion
Criteria Based Upon Diagnostic Assessment
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within 3 months of screening.
- Any subject who, upon oropharyngeal examination, is deemed by the Investigator to be
unsuitable for oropharyngeal sensation assessments. This includes any injuries to the
mucosa of the mouth or pharynx that could potentially increase systemic absorption
e.g. oropharyngeal candidiasis.
- FEV1 less than 80% of the predicted normal value prior to first dosing of the study
- Any subject who does not reach C5 following an oral inhalation of capsaicin at a dose
level of 250 micromolar at screening.
- Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or
nicotine-containing products within 6 months prior to screening.
- A positive pre-study drug/alcohol screen. Other Exclusion Criteria
- Subjects who are unable to use the inhaler satisfactorily.
- Where participation in the study would result in donation of blood or blood products
in excess of 500 mL within a 56 day period.
- Lactating females.
- The subject has participated in a clinical trial and has received an investigational
product within the following time period prior to the first dosing day in the current
study: 30 days, 5 half-lives or twice the duration of the biological effect of the
investigational product (whichever is longer).
- Exposure to more than four new chemical entities within 12 months prior to the first
dosing day.

Study Interventions

Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.

Study Arms

Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.

Part ASubjects will receive treatment A (placebo) or treatment B (GSK2339345) in 3 visits of part A (one treatment per visit) in one of the following four sequences: ABA, ABB, BAA, and BAB.

Part BSubjects will receive treatment A or treatment B in 2 visits of part B (one treatment per visit) in one of the following two sequences: AB and BA. Subjects will then orally inhale 10 microliter (mcL) of a capsaicin solution of strength ranging from 0.49 micromolar (mcM) to 1000 mcM, which will be administered using a breath activated dosimeter approximately 5 minutes post-dosing with treatment A or B at Visits 4 and 5.

Part CSubjects will receive treatment A or treatment B in 2 visits of part C (one treatment per visit) in one of the following two sequences: AB and BA. Subjects will then orally inhale 10 mcL of a citric acid solution of strength ranging from 0.03 to 4.0 M, which will be administered using a breath activated dosimeter approximately 5 minutes post-dosing with treatment A or B at Visits 6 and 7.

Discuss Cough

If you think you may have a medical emergency, call your doctor or 911 immediately.

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